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Functional Links Between Telomeres and Proteins of the DNA-Damage Response

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Functional Links Between Telomeres and Proteins of the DNA-Damage Response Downloaded from genesdev.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Functional links between telomeres and proteins of the DNA-damage response Fabrizio d’Adda di Fagagna,1,3,4 Soo-Hwang Teo,2,3 and Stephen P. Jackson2,5 1IFOM Foundation—The FIRC Institute of Molecular Oncology Foundation, 20139 Milan, Italy; 2The Wellcome Trust and Cancer Research UK Gurdon Institute, and Department of Zoology, University of Cambridge, Cambridge CB2 1QR, UK In response to DNA damage, cells engage a complex set important roles in regulating normal telomeric func- of events that together comprise the DNA-damage re- tions. In this review, we focus on the role of DDR factors sponse (DDR). These events bring about the repair of the in regulating telomere length and stability, and also ex- damage and also slow down or halt cell cycle progression plain how dysfunctional telomeres can trigger the DDR. until the damage has been removed. In stark contrast, Before doing this, however, we first summarize the sa- the ends of linear chromosomes, telomeres, are generally lient features of both telomeres and the DDR. not perceived as DNA damage by the cell even though they terminate the DNA double-helix. Nevertheless, it Telomere structure and biology has become clear over the past few years that many pro- The ends of linear chromosomes contain long stretches teins involved in the DDR, particularly those involved in of DNA tandem repeats (TTAGGG in vertebrates) and responding to DNA double-strand breaks, also play key terminate in a 3Ј protruding single-stranded DNA over- roles in telomere maintenance. In this review, we dis- hang. Due to the inability of the standard lagging-strand cuss the current knowledge of both the telomere and the DNA replication machinery to copy the most distal telo- DDR, and then propose an integrated model for the mere sequences (i.e., those at the very end of the chro- events associated with the metabolism of DNA ends in mosome) and to the additional exonucleolytic processing these two distinct physiological contexts. needed to generate protruding overhangs at both ends, telomeric DNA progressively decreases in length as cells All organisms respond to interruptions in the DNA go through successive division cycles. Hence, in the ab- double-helix by promptly launching the DNA-damage sence of specialized telomere homeostatic mechanisms response (DDR). This involves the mobilization of DNA- this would ultimately lead to the loss of all telomeric repair factors and the activation of pathways, often sequences and subsequently to the loss of more internal termed checkpoint pathways, which temporarily or per- essential genetic information and ensuing cell death. To manently delay cell cycle progression. Although the in- circumvent this, many cells maintain their telomeres by tegrity of the DNA double-helix is perturbed by telo- the action of telomerase, a specialized reverse transcrip- meres (the ends of linear chromosomes), these structures tase that uses its associated RNA component as a tem- generally escape activating the DDR. Several explana- plate to elongate the TG-rich telomeric DNA strand. Al- tions have been proposed to explain the exceptional na- though in vitro telomerase activity is dependent on the ture of telomeres in this regard. Thus, it has been sug- activity of the reverse transcriptase catalytic subunit gested that a telomere might not be recognized by com- (Est2p in the budding yeast Saccharomyces cerevisiae; ponents of the DDR because of its unique DNA TERT in mammals) and the telomerase RNA template sequence and structure, its specific localization within (Tlc1 in S. cerevisiae and hTR in humans), other factors the cell nucleus, and/or because of the actions of specific are clearly needed for telomerase action in vivo (see proteins associated with it. Although this is partly cor- Table 1). For instance, effective telomerase function in S. rect, recent findings have revealed that, contrary to ini- cerevisiae requires Est1p and Est3p, and the loss of either tial expectations, various proteins involved in the DDR of these two proteins—like the loss of Tlc1 or Est2p— physically associate with telomeres and actually play leads to progressive telomere shortening (for review, see Blackburn 2000). Furthermore, and as explained below, effective telomerase action in vivo also requires several [Keywords: Telomere; DNA-damage response; checkpoint; senescence; proteins associated with the DDR. DNA repair] The telomeric repeat sequences are essential for many 3These authors contributed equally to this work. Corresponding authors: of the key biological features of telomeres by virtue of 4E-MAIL [email protected]; FAX 39-02-574303-231. them being recognized by a specific set of sequence- and 5E-MAIL [email protected]; FAX 44-1223-334089. Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/ structure-specific DNA-binding factors (Table 1; Fig. 1). gad.1214504. Some of these bind to the double-stranded portion of the GENES & DEVELOPMENT 18:1781–1799 © 2004 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/04; www.genesdev.org 1781 Downloaded from genesdev.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press d’Adda di Fagagna et al. Table 1. Telomere-associated factors Mammals S. cerevisiae S. pombe C. elegans TRF1: telomere DNA binder Rap1p: telomere length Taz1p: telomere length and and telomerase mediated- regulator structure regulator telomere length regulator Tbf1p: telomere binding factor TIN2: telomerase mediated telomere length regulator TANK1: TRF1 PARP modifier and telomere length regulator TANK2: TRF1 PARP modifier TRF2: telomere DNA binder with telomere end capping function and telomerase independent telomere length regulator RAP1: TRF2 interactor and Rap1p: Taz1p interactor and telomere length regulator telomere length regulator ERCC1/XPF: TRF2 interacting endonuclease MRN complex: TRF2 interactor MRX complex: telomere length MRN: in vivo component of and single stranded overhang the telomere and telomere regulator length regulator Rif1: Trf2 interactor and in Rif1/2p: Rap1p interactors and Rif1p: Taz1p interactor and vivo component of mouse telomere length regulators telomere length regulator telomeres POT1: TRF1 interactor and Cdc13p: single stranded Pot1p: single stranded single stranded telomeric telomeric DNA binder with telomeric DNA binder DNA binder with telomere telomere capping and with telomere capping length regulation functions telomerase recruiting functions functions Stn1p/Ten1p: Cdc13p interactors and mediators of its telomerase recruiting and capping functions Ku: in vivo component of the Ku: in vivo component of the Ku: in vivo component of telomere and telomere length telomere, telomere length the telomere and telomere regulator (?) and single-stranded overhang length regulator regulator DNA-PKcs: in vivo component of the telomere with telomere capping functions EST1A/B: telomere length Est1p: in vivo cofactor of Est1p: in vivo cofactor of regulator (?) telomerase telomerase TERT: catalytic component of Est2p: catalytic component of Trt1p: catalytic component the telomerase complex the telomerase complex of the telomerase complex TR: RNA component of the Tlc1: RNA component of the telomerase complex telomerase complex PARP1: telomere length regulator RPA: in vivo component of the telomere with Est1p-recruiting functions 9–1–1 complex: in vivo MRT-2 and Hus1: regulators component of the of telomere length and telomere and telomere germline mortality length regulator Tel2p: telomere length Rad5: telomere length regulator regulator (?) telomeric DNA and are involved in telomere length while others have important roles in capping the very regulation (e.g. S. cerevisiae Rap1p, Schizosaccharomy- end of the chromosome by virtue of their ability to rec- ces pombe Taz1p, and mammalian TRF1 and TRF2), ognize the telomeric 3Ј overhang (e.g., S. cerevisiae 1782 GENES & DEVELOPMENT Downloaded from genesdev.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Telomeres and the DNA-damage response Figure 1. Schematic representation of telomere factors in different organisms. Cdc13, S. pombe Pot1p, and possibly hPOT1). These lat- associated with it, or a combination of both, that is cru- ter factors bind single-stranded DNA through a con- cial for evading the activation of a DDR. In vitro, the served OB (oligonucleotide/oligosaccharide binding) fold mammalian telomere repeat binding protein, TRF2, can domain (Mitton-Fry et al. 2002; Lei et al. 2003) and be- promote T-loop formation (Stansel et al. 2001), and im- cause a DDR ensues in their absence, are believed to play pairing the DNA-binding function of TRF2 in vivo leads crucial roles in preventing the inappropriate triggering of to either ataxia telangiectasia mutated (ATM)- and p53- the DDR by the telomere. Indeed, in S. cerevisiae lacking dependent cell death or to permanent cell cycle arrest, functional Cdc13p, the CA-rich telomeric strand depending on the cell type (Karlseder et al. 1999). Al- complementary to that bound by Cdc13p is rapidly de- though T loops have so far only been demonstrated in graded, leading to RAD9-dependent cell-cycle arrest mammals and Trypanosomes (Munoz-Jordan et al. 2001), (Garvik et al. 1995; see below). Similarly, inactivation of similar structures may exist in other organisms. In S. S. pombe Pot1p leads to rapid and dramatic telomere cerevisiae, evidence has been provided that telomeric shortening,
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